Type 2 diabetes is increasingly common, is developing at an earlier age and causing devastating complications to many Americans (25 million already have the disease and another 25 million are at high risk). The underlying cause of the disease is a failure of the pancreas to make sufficient insulin, a hormone that regulates the blood glucose levels and prevents diabetes. This competitive renewal seeks continued funding of a research group at the Hillblom Islet Research Center at UCLA to support our efforts to establish the underlying cause of failure of the cells that make and secrete insulin in type 2 diabetes, and in doing so to develop new approaches to treatment of this disease. Our focus is on the role of small tangles of proteins called oligomers that form in the pancreatic beta cells that make and secrete insulin in people who develop type 2 diabetes. Our work has shown that in people with type 2 diabetes these tangles cause leakage of the cell membranes that allows calcium ions into compartments of the cell that are not appropriate and drives the activation of enzymes that inappropriately remodel the cells protein skeleton (cytoskeleton) causing a series of subsequent damaging alterations into how the cell functions as well as limiting the ability of the cell to repair itself. The mitochondria are particularly vulnerable to this damage. We propose studies to investigate these processes and to test a new approach to treating type 2 diabetes, in particular, to blunt the undesirable cytoskeleton remodeling.